(1) Field of the Invention
This invention relates in general to the activity of interferon.gamma. (IFN.gamma.), and more particularly to a composition capable of the intracellular inhibition of an interferon.gamma. activatable transcription factor that is involved in the activation of interferon.gamma. inducible genes, and a method for inhibiting such a transcription factor.
(2) Description of Background Art
Interferon-.gamma. (IFN.gamma.) is an important cytokine derived from T cells and natural killer cells that plays important roles in promoting host defense and immunopathologic processes. IFN.gamma. exerts its pleiotropic effects on cells through an interaction with a specific high affinity receptor expressed at the cell surface. Functionally active receptors require the presence of two distinct species specific polypeptides: a 90 kDa .alpha. chain that is both necessary and sufficient for IFN.gamma. binding and processing and necessary but not sufficient for biologic response induction, and a second recently cloned polypeptide now denoted as the IFN.gamma. receptor .beta. chain needed exclusively for development of functional responses in cells (Jung et al., 1987; Jung et al., 1990; Fischer et al., 1990; Farrar et al. 1991; Gibbs et al., 1991). Although the function of the receptor .beta. chain remains entirely unclear, the structure-function relationships that exist within the receptor a chain have been the focus of a number of recent studies (Farrar et al., 1991; Farrar et al., 1992). Specifically, these analyses have revealed two topographically distinct, functionally important regions within the receptor .alpha. chain's intracellular domain. The first is comprised of 48 amino acids, proximal to the receptor's transmembrane domain (amino acids 256-303), and contains elements required for both receptor-mediated ligand internalization and biologic response induction (enhancement of MHC class I expression) (Farrar et al., 1991). The second region is located near the receptor's carboxy terminus, distal to the transmembrane region, and includes three closely spaced amino acids, Y440, D441, and H444, which are required exclusively for biologic responsiveness (Farrar et al., 1992).
The increased understanding of the structure and function of the IFN.gamma. receptor has coincided with an explosive growth in understanding of the intracellular molecular events that underlie IFN.gamma. dependent signal transduction. Recently IFN.gamma. has been shown to induce in cells the phosphorylation and activation of a family of latent SH2 domain containing cytoplasmic transcription factors, such as the protein identified as p91. Activation of p91 effects the assembly of an active p91-containing multimolecular transcription factor complex which translocates to the nucleus and binds to specific sequences in the promoters of IFN.gamma. inducible genes, thereby initiating gene transcription (Decker et al., 1991; Schindler et al., 1992; Fu et al., 1993; Shuai et al., 1993; Pearse et al., 1993). Although these observations have substantially enhanced the understanding of IFN.gamma. signal transduction, they have not defined the molecular mechanisms coupling the IFN.gamma. receptor to p91 activation.
IFN.gamma. is also known to be a potent activator of monocytes and macrophages and is, therefore, a critical component for host defense and the inflammation response. The secretion of IFN.gamma. elicits the induction of numerous genes that encode for proteins that can act as soluble, secreted mediators of inflammation, such as IL-8 and IP-10, and other receptor proteins that are crucial for immune responsiveness and host defense. IFN.gamma. is, therefore, believed to contribute to the adverse effects of inflammatory diseases and autoimmune diseases because of its significant gene inducible characteristics. It would be advantageous, therefore, to identify a means for inhibiting the inducible gene transcription activity of IFN.gamma. and thereby inhibit the activation of the IFN.gamma. inducible genes and the resulting cellular response in a direct and specific manner. The identification of such a means would be useful as a therapeutic treatment for autoimmune and inflammatory diseases and for the treatment of cancer.